Less-Intensive Leukemia Regimen Outperforms Standard Chemo

A combination of azacitidine and venetoclax kept patients with acute myeloid leukemia (AML) free of relapse or disease progression or other treatment failure more than twice as long as standard induction chemotherapy, according to results of a randomized phase 2 trial published online today in the New England Journal of Medicine.¹

The PARADIGM trial (NCT04801797) found that patients assigned to azacitidine-venetoclax had a median event-free survival (EFS) of 14.5 months (95% CI, 10.4-24.4) vs 6.2 months (95% CI, 4.1-10.1) for patients who received induction chemotherapy, an intensive decades-old standard treatment built around cytarabine and anthracycline drugs. This difference translated to a 43% reduction in risk of relapse, treatment failure, or death (HR, 0.57; 95% CI, 0.39-0.84; P = .002).

“In my humble opinion, it should,” said Amir T. Fathi, MD, the study’s first author and director of the leukemia program at the Mass General Brigham Cancer Institute, in an interview with The American Journal of Managed Care^® when asked if this difference is significant enough to change how induction-eligible patients are treated. “This is not a registrational, randomized phase 3 study, but it is a randomized phase 2 study that was meant to detect the relative efficacy of a more gentle approach vs a traditional, more intensive approach.” He added that the gentler regimen also made patients less likely to be refractory or have persistent disease, meaning more of them could reach transplant, which he called the ultimate curative path for patients with intermediate- or adverse-risk disease. “If you can get there easier, why shouldn’t you?”

The findings are notable because azacitidine-venetoclax, a hypomethylating agent (HMA) and a targeted BCL-2 inhibitor, has until now been reserved mostly for older or medically frailer patients who cannot tolerate induction chemotherapy. PARADIGM instead enrolled patients who were considered fit and eligible for intensive treatment and then tested whether the gentler combination could still outperform it.

A High-Risk Population, Evenly Split

The trial randomly assigned 172 adults with previously untreated AML across 9 US academic centers, with 86 patients in each arm. This population is skewed toward higher-risk disease than is typical in AML trials: 72% of participants had adverse-risk disease by 2022 European LeukemiaNet criteria, and more than half had AML that arose from myelodysplasia-related changes. Median patient age was 64 years (range, 23-79), with just over half of the patients younger than 65 years. Men comprised close to two-thirds of each arm, and the racial and ethnic composition—6% Black, 8% Hispanic, 9% Asian, and 78% White—was described by the investigators as representative of the US AML population.

Patients with certain more treatable genetic subtypes—core binding factor fusions, FLT3 mutations, and NPM1 mutations in patients younger than 60 years—were excluded, since those groups already have approved targeted therapies and established induction-based standards of care. That exclusion guidance shaped the study population toward higher-risk, harder-to-treat disease.

Fathi argues the exclusions cut the other way, too. “Testing for FLT3 mutations or NPM1 mutations or core-binding factor alteration should be routine enough if you are truly caring for patients who have AML,” since missing those mutations means missing FDA-approved treatments those patients would otherwise receive. Until dedicated trials study those subgroups, he said, “the data that we have should not apply to them.”

He has pointed to the earlier VIALE-A trial (NCT02993523), which established azacitidine-venetoclax as standard therapy for patients ineligible for intensive chemotherapy, as the basis for testing the combination in fit patients as well. Retrospective studies had hinted the regimen might also help fit patients, he has said, but no randomized trial had confirmed it.²

How Did the Safety Profiles Differ?

Severe (grade 3 or higher) infections occurred in 28% (95% CI, 19%-39%) of patients on azacitidine-venetoclax vs 41% (95% CI, 30%-52%) on induction chemotherapy, and severe bleeding occurred in 2% (95% CI, 0.3%-8.0%) vs 12% (95% CI, 6%-20%), respectively. No patients in the azacitidine-venetoclax cohort died within 30 or 60 days of starting treatment compared with 3% and 5% mortality at those time points in the chemotherapy cohort. The lower-intensity regimen also kept patients out of the hospital more. In the first 30 days, patients on azacitidine-venetoclax averaged 12.5 inpatient days vs 27.3 for those on induction chemotherapy, and none required intensive care compared with 10% of the chemotherapy group.

Despite the differences in EFS and hospitalization, overall survival (OS) was similar between the arms: 21.5 months vs 18.0 months, a finding the authors partially attributed to the fact that many patients who progressed on one treatment went on to receive the other as salvage therapy and partly to the trial not being statistically powered to detect an OS difference.

A key secondary finding was that 60% of patients on azacitidine-venetoclax proceeded to hematopoietic-cell transplantation compared with 40% on induction chemotherapy, despite the majority of the study population having adverse-risk disease that would typically be considered difficult to bring into remission with a lower-intensity approach.

“More patients actually responded to HMA-Ven than they did to intensive chemotherapy, and you need to have a response to get to transplant,” Fathi said. He noted that lower early mortality with the gentler regimen probably helped a subset of patients reach transplant as well, “but for others, it was that they got a response, whereas those on the intensive therapy arm were less likely to respond.”

Overall, the authors caution that the results should not be extended to patients with favorable-risk disease, FLT3 mutations, or NPM1 mutations. They also note that the trial was conducted at academic centers without blinded, centralized review of outcomes and call for further studies before broader practice change, including ones incorporating targeted therapies.

Asked what he’d want to see from a larger, confirmatory phase 3 trial, Fathi said he hopes the field moves away from OS as a primary end point in AML studies where crossover is common and patients aren’t blinded to their assigned treatment. “I say we may not be able to demonstrate that [patients live longer], and they may not live longer, but they live better,” he said. “It’s much better for somebody to go through a therapy and not have to relapse once or twice, or not get multiple lines of treatment, or have toxicity or challenges with treatment. The context matters.”

References

1. Fathi AT, Perl AE, Fell GG, et al. Azacitidine–venetoclax or induction chemotherapy for acute myeloid leukemia. N Engl J Med. 2026;395(9): 845-858. doi:10.1056/NEJMoa2602804
2. Caffrey M. Azacitidine/venetoclax combo data challenge chemo in fit patients with AML. AJMC^®. December 8, 2025. Accessed September 2, 2026. https://www.ajmc.com/view/data-could-let-azacitidine-and-venetoclax-challenge-chemo-for-treatment-of-fit-patients-with-aml